Project Summary/Abstract Myocardial infarction (MI) continues to be one of the leading causes of death in the world due to the negative tissue remodeling that takes place post-MI and leads to heart failure (HF). Methods to treat the heart immediately after MI and prevent negative remodeling are needed to improve patient outcomes and increase long-term survival. The goal of this proposal is to develop a novel therapeutic delivery system to non-invasively and safely target treatment to the infarct immediately after MI. Such a system is needed to avoid the off-target side effects that occur when therapeutics are delivered systemically and to allow for intravenous administration rather than direct injection into the damaged heart tissue as is necessary for many other delivery systems being developed. Enzyme-responsive nanoparticles are a promising approach. These nanoparticles respond to matrix metalloproteinases (MMPs), enzymes that are up regulated in the infarct post-MI and help drive negative remodeling and subsequent HF. Previous work showed that they can be injected intravenously and will accumulate in the infarct. This proposal seeks to build on previous work and develop these nanoparticles for non- invasive and safe drug delivery to the infarct. The first aim of this proposal is to redesign the nanoparticles to provide for elimination from the tissue after accumulation and to assess their safety. A cleavable core will be incorporated into the nanoparticles to facilitate elimination. Core cleavage will be assessed in vitro prior to testing in a rat model of MI. Toxicity studies will be done in vitro with heart muscle cells and in the animals by checking for an inflammatory response, evaluating liver and kidney function, and analyzing blood cell counts. Accumulation followed by elimination and the potential to cause arrhythmia will also be assessed in the rat model. The second aim of the proposal is to study the MMP-responsive nanoparticles as a delivery vehicle for MMP inhibitors. Studies show that MMP inhibitors limit the negative remodeling in animals but they have not been amenable to systemic use in humans because of off-target side effects. Thus, MMP inhibitors will be conjugated to the nanoparticle core by a labile chemical bond so that after accumulation in the infarct the inhibitor is released. Functional MMP inhibitor release will be assessed in vitro. Then the ability to use the nanoparticle to deliver the MMP inhibitor to the infarct and improve tissue recovery will be studied in the rat model of MI. This proposal aims to develop a novel, non-invasive, and safe strategy to target delivery of a therapeutic to the infarct to support tissue repair. If successful, this work has the potential to revolutionize MI treatment and significantly improve the lives of MI patients.